Fundamental questions regarding the long-term health of children conceived in vivo during poor maternal health or adverse lifestyle choices, or conceived ex vivo in the course of infertility treatment, remain unanswered and are logistically difficult to resolve. The relationship between human fetal development and the risk of adult onset diseases, including Type II diabetes and cardiovascular disease, has been well described. Our laboratory and others have shown, in animal models, that the external microenvironment surrounding the early embryo significantly influences subsequent fetal development (""""""""embryonic programming""""""""). What remains unclear is the association between embryonic programming and potential risks of adult onset disease. In addition, the influence of the microenvironment during oocyte maturation, on embryonic programming and fetal development, is very poorly understood. Recent evidence implicates that some of the effects of adverse oocyte and embryo microenvironments are mediated by disturbed methylation of imprinted genes. Our previous work suggests that altered methylation alone cannot account for the range of fetal phenotypes observed. Our hypothesis is that adverse micro environments cause cellular stress within oocytes and embryos, which significantly induces a range of molecular and biochemical responses that impinge on embryo growth and implantation events, leading to an altered fetal phenotype. Several different approaches, all utilizing established animal models, will be used to test this hypothesis. These are: (1) determining the effect of cellular and molecular consequences of hypoxic stress on follicular enclosed oocytes, (2) describing the effect of hypoxia-induced gene expression in embryos on fetal development, (3) determining the role of nitrogenous nutrition during embryo development in eliciting ammonia-mediated stress, and (4) elucidating the cellular and molecular mechanisms within early embryos through which the growth factor milieu influences fetal development and neo-natal outcomes. By understanding the effect of the microenvironment on cellular and molecular behavior of oocytes and embryos, stress-induced responses can be minimized, improving the developmental outcomes for both mothers and babies. This knowledge will also assist health professionals develop strategies to reduce the risk of adult onset diseases caused by perturbed early development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HD044664-02
Application #
6800760
Study Section
Special Emphasis Panel (ZHD1-DRG-D (18))
Program Officer
Rankin, Tracy L
Project Start
2003-09-11
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$247,572
Indirect Cost
Name
University of Adelaide
Department
Type
DUNS #
756220182
City
Adelaide
State
Country
Australia
Zip Code
5034
Schelbach, Cheryl J; Robker, Rebecca L; Bennett, Brenton D et al. (2013) Altered pregnancy outcomes in mice following treatment with the hyperglycaemia mimetic, glucosamine, during the periconception period. Reprod Fertil Dev 25:405-16
Sutton-McDowall, Melanie L; Gilchrist, Robert B; Thompson, Jeremy G (2010) The pivotal role of glucose metabolism in determining oocyte developmental competence. Reproduction 139:685-95
Schelbach, Cheryl J; Kind, Karen L; Lane, Michelle et al. (2010) Mechanisms contributing to the reduced developmental competence of glucosamine-exposed mouse oocytes. Reprod Fertil Dev 22:771-9
Jansen, Sarah; Cashman, Kara; Thompson, Jeremy G et al. (2009) Glucose deprivation, oxidative stress and peroxisome proliferator-activated receptor-alpha (PPARA) cause peroxisome proliferation in preimplantation mouse embryos. Reproduction 138:493-505
Banwell, Kelly M; Thompson, Jeremy G (2008) In vitro maturation of Mammalian oocytes: outcomes and consequences. Semin Reprod Med 26:162-74
Pringle, K G; Kind, K L; Thompson, J G et al. (2007) Complex interactions between hypoxia inducible factors, insulin-like growth factor-II and oxygen in early murine trophoblasts. Placenta 28:1147-57
Banwell, K M; Lane, M; Russell, D L et al. (2007) Oxygen concentration during mouse oocyte in vitro maturation affects embryo and fetal development. Hum Reprod 22:2768-75
Pringle, K G; Roberts, C T (2007) New light on early post-implantation pregnancy in the mouse: roles for insulin-like growth factor-II (IGF-II)? Placenta 28:286-97
Thompson, Jeremy G B; Mitchell, Megan; Kind, Karen L (2007) Embryo culture and long-term consequences. Reprod Fertil Dev 19:43-52
Feil, Deanne; Lane, Michelle; Roberts, Claire T et al. (2006) Effect of culturing mouse embryos under different oxygen concentrations on subsequent fetal and placental development. J Physiol 572:87-96

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